Macrophages: Targets for next-generation cancer immunotherapy

Tumor-associated macrophages (TAM) are among the most abundant immune cells in tumors and exhibit striking functional plasticity, enabling them to either promote tumor progression or mediate malignant cell elimination. This paradox arises from TAM heterogeneity shaped by diverse developmental origins, transcriptional programs, and microenvironmental cues. Here, we review next-generation strategies to therapeutically target TAMs, with dual goals of relieving macrophage-driven immunosuppression and unleashing their tumoricidal potential. These approaches include effectorization by modulating “eat-me” pathways and targeted activation, as well as reprogramming TAMs through inhibiting immune checkpoints, rewiring signaling, epigenetics, and metabolism, and targeting myeloid progenitors at sites of hematopoiesis. We also discuss advances in bioengineering, including bispecific antibodies, masked cytokines, genetic engineering, targeted lipid nanoparticles and anti-TAM CAR T cells, that enable increasingly precise control of macrophage biology. These therapies have transformative potential to enhance tumor-specific T cells, and provide an independent alternative arm of immunity, to enable durable cancer eradication.